The widespread use of alcohol results in serious societal problems, and a significant component of its abuse is damage to the integrity of the nervous system. The focus of this study is the evaluation of means by which such adverse effects might be attenuated. The concept underlying this research is that ethanol or its major metabolite, acetaldehyde, may disrupt membrane function by non- specific or by more selective damage. This insult may occur at the plasma membrane but may also involve the integrity and functioning of the endoplasnlic reticulum or mitochondrion. The ability of ethanol or acetaldehyde to disrupt cellular homeostasis will initially be studied by in vitro exposure of isolated synaptosomes to these agents. These studies will be supplemented later by studies of morphological fractions derived from ethanol or acetaldehyde-treated rats. Evaluation of cytotoxic events will be by use of several fluorescent probes which allow continuous monitoring of various indices of metabolic and structural integrity. Parameters include determination of transmembrane potentials across plasma and mitochondrial membranes, cytoplasmic pH and redox status, and microviscosity of the synaptosomal limiting membrane. In addition, free-radical induced oxidative activity will be assayed. Preliminary work has revealed that a metabolite of ethanol (acetaldehyde) can enhance generation of reactive oxygen species. Pretreatment with certain chemicals has been found to prevent synaptosomal deterioration induced by several xenobiotic agents. Tbe major putative protective materials to be studied are: a lipid soluble antioxidant vitamin, alpha-tocopherol; monosialoganglioside GM1 and an antagonist of n-methyl-d-aspartic acid (MK-801), the diamine product of ornithine decarboxylation (putrescine), and thiamine. The in vitro studies will be of value in further definition of the molecular lesions induced by ethanol, while the corresponding in vivo studies may contribute to the conceptual development of therapies for alcohol-related disease.